Trauma and Genomics Modulate Brain Structure across Common Psychiatric Disorders

创伤和基因组学调节常见精神疾病的大脑结构

• 批准号: 9389397
• 负责人: MARK W LOGUE
• 金额: $ 47.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9389397
• 关键词: Adult; Amygdaloid structure; Anxiety Disorders; Architecture; Area; Arousal; Automobile Driving; Behavior; Big Data; Bioinformatics; Bipolar Disorder; Brain; Child; Childhood; Clinical Paths; Collaborations; Corpus striatum structure; Data; Disease; Environment; Evaluation; Exposure to; Extinction (Psychology); Fright; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Goals; Heritability; Hippocampus (Brain); Human; Individual; Intervention; Lead; Life; Magnetic Resonance Imaging; Measures; Medial; Memory; Mental Depression; Mental disorders; Meta-Analysis; Methodology; Molecular; Molecular Genetics; Mood Disorders; Morphology; Neurobiology; Participant; Pathogenesis; Pathology; Pathway interactions; Phenotype; Post-Traumatic Stress Disorders; Psychopathology; Research Domain Criteria; Risk; Risk Factors; Sampling; Shapes; Site; Structure; Surface; Symptoms; Thick; Trauma; abuse neglect; base; brain pathway; clinical phenotype; deep sequencing; endophenotype; gene discovery; genetic risk factor; genetic variant; genome wide association study; inattention; neuroimaging; new therapeutic target; pediatric trauma; psychogenetics; psychological trauma; tool; white matter; whole genome; working group

ABSTRACT Exposure to trauma and abuse during childhood, a critical neurodevelopmental period, is a major risk factor for adult psychopathology. However, not all children exposed to childhood trauma will develop adult psychopathology. Variability in the risk for trauma-related pathology is expected to arise in part from genetic susceptibility. Several genes have recently been identified that interact with childhood trauma to increase rates of anxiety and mood disorders in adulthood. This risk can be more easily detected by examining endophenotypes such as brain measures obtained from MRI because of a simpler underlying genetic architecture with fewer individual genes or pathways than the multiple factors driving overall risk for psychopathology. Understanding the molecular-genetic contributors to brain structure that conspire with early-life environment (psychological trauma) and lead to adult psychopathology, will require large-scale collaborative efforts which harness big-data methodologies. Our goal is to conduct a GWAS of relevant structural brain measures in individuals exposed to childhood trauma, with the long-term goal of identifying genetic modulators of brain structure that are informative for early prediction and treatment for a range of psychiatric disorders where childhood trauma is a major risk factor. We hypothesize that (1) childhood trauma will interact with specific genetic markers to produce structural brain alterations and adult psychopathology, (2) that unique genetic variants, in the context of genetic vulnerability to childhood trauma, will influence the onset of specific disorders (e.g. depression vs PTSD), as well as (3) the presentation of specific symptom constructs (e.g. sustained threat) across disorders. Finding disease-associated genetic variation that point to molecular mechanisms of pathogenesis has proven challenging due to the polygenicity of clinical phenotypes. Leveraging neuroimaging phenotypes may offer a more direct path than clinical phenotypes in identifying these elusive genetic markers and relevant neurobiological pathways. Ultimately, the promise of finding genetic contributors of any psychiatric disorder is in identifying the presence of new biologic pathways for which targeted interventions may be devised and deployed.

抽象的 童年时期是神经发育的关键时期，遭受创伤和虐待是一个主要的危险因素 用于成人精神病理学。然而，并非所有遭受童年创伤的儿童都会长大成人 精神病理学。创伤相关病理风险的变异预计部分由遗传因素引起 易感性。最近发现了几个与童年创伤相互作用的基因，以提高发病率 成年期的焦虑和情绪障碍。通过检查可以更容易地发现这种风险 内表型，例如由于更简单的潜在遗传而从 MRI 获得的大脑测量结果 与驱动总体风险的多个因素相比，单个基因或途径更少的架构 精神病理学。了解大脑结构的分子遗传因素 早期生活环境（心理创伤）并导致成人精神病理学，将需要大规模 利用大数据方法的协作努力。我们的目标是开展相关的 GWAS 对遭受童年创伤的个体进行结构性大脑测量，长期目标是识别 大脑结构的遗传调节剂，可为一系列疾病的早期预测和治疗提供信息 童年创伤是主要危险因素的精神疾病。我们假设（1）童年创伤 将与特定的遗传标记相互作用，产生大脑结构改变和成人精神病理学， (2) 在遗传易受童年创伤的背景下，独特的遗传变异将影响 特定疾病的发作（例如抑郁症与创伤后应激障碍），以及 (3) 特定症状的表现 跨疾病的构建（例如持续的威胁）。寻找与疾病相关的遗传变异 由于临床表型的多基因性，发病机制的分子机制已被证明具有挑战性。 利用神经影像表型可能提供比临床表型更直接的途径来识别 这些难以捉摸的遗传标记和相关的神经生物学途径。最终，找到基因的希望 任何精神疾病的贡献者都在识别新的生物途径的存在，这些途径的存在 可以设计和部署有针对性的干预措施。